MICROVASCULAR REMODELING IN CHRONIC AIRWAY INFLAMMATION

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Project P-4 will examine mechanisms, consequences, and reversibility of microvascular remodeling in chronic inflammation of the airways. Drs. McDonald, Baluk, and Thurston will use Mycoplasma pulmonis infection in normal and genetically altered mice and in rats as models to characterize the angiogenesis and microvascular enlargement that occur in chronic airway inflammation. The overall hypothesis is that different patterns of endothelial cell specific growth factors and cytokines produced in inflamed airways can cause different types of abnormalities in the microvasculature and that these abnormalities, when unchecked, favor the perpetuation of the inflammatory response. The project has four specific aims. (1) The first aim is to characterize the new capillary-like vessels (angiogenesis) and remodeled venule-like vessels (microvascular enlargement) that form in chronic airway inflammation in mice with different genetic backgrounds. These experiments will test the hypothesis that the amounts of angiogenesis and microvascular enlargement in chronic inflammation are governed by genetic determinants of the host innate and acquired immunologic response. (2) The second aim is to determine the cellular location and effects of two angiogenic growth factors (vascular endothelial growth factor, Angiopoietin-1) and their receptors to test the hypothesis that the relative amounts of angiogenesis and microvascular enlargement in chronically inflamed airways result from different patterns of these endothelial cell-specific growth factors. (3) The third aim is to determine the mechanism of plasma leakage in chronic airway inflammation and the role of VEGF in this leakage. These studies will test the hypothesis that the sustained plasma leakage in chronic inflammation is due to increased expression of VEGF or VEGF receptors, which result in the formation of intercellular gaps in the endothelium of remodeled vessels. (4) The final aim is to examine the reversibility of the vascular remodeling. These studies will test the hypothesis that the vasculature is a potential therapeutic target, and reversal of the microvascular remodeling can interrupt the plasma leakage and inflammatory cell influx that sustain the inflammatory response. The rationale for this project is that our experience with the M. pulmonis model of chronic airway inflammation in mice and rats combined with novel methods for studying the airway vasculature will provide new insights into the mechanisms and consequences of microvascular remodeling in chronic inflammatory airway disease. The project has the significance of exploring the feasibility of using the microvasculature as a therapeutic target in chronic inflammatory diseases of the respiratory tract, and of obtaining a more detailed understanding of mycoplasma-induced airway disease, which may be a contributing factor in asthma.